Indole-3-Sulphur Derivatives

ABSTRACT

The present invention relates to substituted indoles useful as pharmaceutical compounds for treating respiratory disorders. (I)

The present invention relates to substituted indoles useful aspharmaceutical compounds for treating respiratory disorders,pharmaceutical compositions containing them, and processes for theirpreparation.

EPA 1 170 594 discloses methods for the identification of compoundsuseful for the treatment of disease states mediated by prostaglandin D2,a ligand for orphan receptor CRTh2. GB 1356834 discloses a series ofcompounds said to possess anti-inflammatory, to analgesic andantipyretic activity. It has now surprisingly been found that certainindole acetic acids are active at the CRTh2 receptor, and as aconsequence are expected to be potentially useful for the treatment ofvarious respiratory diseases, including asthma and COPD.

In a first aspect the invention therefore provides a compound of formula(I) or a pharmaceutically acceptable salt thereof:

in which:n represents 1 or 2;R¹ is one or more substituents independently selected from halogen, CN,nitro, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴,NR⁹CO₂R⁴, NR⁹COR⁴, aryl, heteroaryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₁₋₆alkyl, the latter five groups being optionally substituted by one ormore substituents independently selected from halogen, OR⁷ and NR⁸R⁹,NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1 or 2;R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, COR⁴ or C₁₋₇alkyl, thelatter group being optionally substituted by one or more substituentsindependently selected from halogen atoms, OR⁸ and NR⁵R⁶, S(O)_(x)R⁷where x is 0, 1 or 2;R³ is aryl or a 5-7 membered heteroaryl ring containing one or moreheteroatoms selected from N, S and O, each of which is optionallysubstituted by one or more substituents independently selected fromhalogen, CN, nitro, SO₂R⁴, OH, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶,NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl,the latter three groups being optionally substituted by one or moresubstituents to independently selected from halogen atoms, OR⁷ andNR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1 or 2;R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl, all of which may beoptionally substituted by one or more substituents independentlyselected from halogen atoms, aryl, heteroaryl, OR¹⁰ andNR¹¹R¹²S(O)_(x)R¹³ (where x=0, 1 or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵,SO₂NR¹⁴R¹⁵, is NR¹⁴SO₂R¹⁵, CN, nitro;R⁵ and R⁶ independently represent a hydrogen atom, a C₁-C₆ alkyl group,an aryl, or a heteroaryl, the latter three of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, aryl, OR¹³ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,NR¹⁴SO₂R¹⁵, CN, nitro;orR⁵ and R⁶ together with the nitrogen atom to which they are attached canform a 3-8 membered saturated heterocylic ring optionally containing oneor more atoms selected from O, S(O)_(x), where x is 0, 1 or 2, NR¹⁶, andthe ring itself optionally substituted by C₁-C₃ alkyl;R⁷ and R¹³ independently represent a C₁-C₆ alkyl group, an aryl orheteroaryl group all of which may be optionally substituted by halogenatoms;R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionallysubstituted by halogen atoms, aryl or heteraryl groups, both of whichmay also be optionally substituted by one or more fluorine atoms); anaryl or a heteroaryl group, which may be optionally substituted by oneor more halogen atoms;each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a hydrogenatom, C₁-C₆ alkyl, an aryl or a heteroaryl group (all of which may beoptionally substituted by one or more halogen atoms); andR¹⁶ is hydrogen, C₁₋₄ alkyl, —C(O)C₁-C₄ alkyl, C(O)YC₁-C₄alkyl, Y is Oor NR⁷.

In the context of the present specification, unless otherwise indicated,an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituentgroup may be linear, branched or cyclic.

Aryl is phenyl and naphthyl.

When R³ is heteroaryl, examples include pyridine, pyrimidine, thiazole,oxazole, pyrazole, imidazole, furan, isoxazole, pyrrole, isothiazole andazulene.

When R⁴ is heteroaryl this includes 5-7 membered aromatic rings or canbe a 6,6- or 6,5-fused bicyclic ring system, each ring containing one ormore heteroatoms selected from N, S and O. Examples include pyridine,pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazole,pyrrole, isothiazole and azulene, naphthyl, indene, quinoline,isoquinoline, indole, indolizine, benzo[b]furan, benzo[b]thiophene,1H-indazole, benzimidazole, benzthiazole, benzoxazole, purine,4H-quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline,1,8-naphthyridine, pteridine, quinolone.

Heterocyclic rings as defined for R⁵ and R⁶ means saturatedheterocycles, examples include morpholine, thiomorpholine, azetidine,imidazolidine, pyrrolidine, piperidine and piperazine.

Preferably n is 2.

Preferably R¹ is halogen, nitrile, C₁₋₆alkyl or SO₂R⁴, NO₂, NR⁹COR⁴,NR⁹SO₂R⁴, aryl, NR⁵R⁶. More preferably R¹ is methyl, nitrile, chloro,SO₂Me, SO₂Et, NHCOR⁴, NHSO₂R⁴, phenyl, NH(alkyl).

The R¹ group(s) can be present at any suitable position on the indolering, preferably the R¹ group(s) is (are) at the 5-position and/or4-position. Preferably the number of substituents R¹ other than hydrogenis 1 or 2.

Preferably R² is C₁₋₆alkyl, more preferably methyl.

Preferably R³ is phenyl optionally substituted by halogen, alkyl, alkoxyor nitrile. More preferably R³ is chloro, methyl, ethyl, cyano ormethoxy.

Substituents can be present on any suitable position of an R³ group.

Preferred compounds of the invention include:

-   3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid;-   6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid;-   7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid;-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acetic    acid;-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;-   3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic    acid;-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid, sodium salt;-   4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   3-[(2-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   3-[(3-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   3-[(4-cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;-   3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic acid;-   3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;-   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic    acid;-   4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-acetic    acid;-   3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic    acid-   3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic    acid,-   3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic    acid,-   5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-acetic    acid,    and pharmaceutically acceptable salts thereof.

In a further aspect the invention provides a sub-class of compounds offormula (IA):

in whichR¹ and R² are independently hydrogen, halogen, CN, amino, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, SO₂C₁₋₆alkyl or CONR⁴R⁵ where R⁴ and R⁵independently hydrogen or C₁₋₆alkyl; andR³ is phenyl substituted by halogen,and pharmaceutically acceptable salts thereof.

Preferably for compounds (IA) R¹ is hydrogen or C₁₋₆alkyl. Morepreferably R¹ is methyl. The R¹ group can be present at any suitableposition on the indole ring, preferably the R¹ group is at the5-position.

Preferably for compounds (IA) R² is C₁₋₆alkyl, more preferably methyl.

Preferably for compounds (IA) R³ is phenyl substituted by chloro.

Preferred compounds (IA) include:

-   {3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-yl}acetic    acid.    and pharmaceutically acceptable salts thereof.

In a further aspect the invention provides a further sub-class ofcompounds of formula (IB):

in which:n represents 1 or 2;R¹ is halogen, CN, nitro, SO₂R⁴, OR⁴, SR⁴, SO₂R⁴, SO₂NR⁵R⁶, CONR⁵R⁶,NR⁵R⁶, NR⁷SO₂R⁴, NR⁷CO₂R⁴, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁₋₆ alkyl,the latter three groups being optionally substituted by one or moresubstituents independently selected from halogen, —OR⁷ and —NR⁸R⁹,S(O)xR⁷ where x is 0, 1 or 2;p is 0 to 4;R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, COR⁴ or C₁₋₇alkyl, thelatter three groups being optionally substituted by one or moresubstituents independently selected from halogen atoms, —OR⁷ and —NR⁸R⁹,S(O)xR⁷ where x is 0, 1 or 2:R³ is R³ is phenyl optionally substituted by halogen;R⁴ represents hydrogen or C₁₋₆alkyl which may be optionally substitutedby one or more substituents independently selected from halogen atoms,aryl, —OR¹⁰ and —NR¹¹R¹².R⁵ and R⁶ independently represent a hydrogen atom, a C₁₋₆alkyl group, orphenyl group the latter two of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, aryl, —OR¹³ and —NR¹⁴R¹⁵, —CONR¹⁴R¹⁵, —NR¹⁴COR¹⁵, —SO₂NR¹⁴R¹⁵,NR¹⁴SO₂R¹⁵;orR⁵ and R⁶ together with the nitrogen atom to which they are attached canform a 3-8 membered saturated heterocylic ring optionally containing oneor more atoms selected from O, S, NR¹⁶, and itself optionallysubstituted by C₁₋₃ alkyl, halogen;each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹², R¹³, R¹⁴, R¹⁵,independently represents a hydrogen atom, C₁-C₆, alkyl, or an arylgroup; andR¹⁶ is hydrogen, C₁₋₄ alkyl, —COC₁-C₄ alkyl, —COYC₁-C₄alkyl, Y═O or NR⁷.

Preferably for compounds (IB) R¹ is halogen, nitrile, C₁₋₆alkyl orSO₂R⁴. More preferably R¹ is methyl, nitrile, chloro, SO₂Me, SO₂Et.Preferably p is 1 or 2.

The R¹ groups can be present at any suitable position on the indolering. preferably the R¹ group(s) is (are) at the 5-position and/or4-position.

Preferably for compounds (IB) R² is C₁₋₆alkyl, more preferably methyl.

Preferably for compounds (IB) R³ is phenyl optionally substituted byhalogen, more preferably chloro.

Preferred compounds (18) include:

-   {3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-yl}acetic    acid,-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid,-   6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid,-   7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic    acid,-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acetic    acid,-   5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic    acid,-   3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid,-   3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic    acid,-   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic    acid,-   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic    acid,-   Sodium    5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetate,    and pharmaceutically acceptable salts thereof.

In a still further aspect the invention provides the use of a compoundof formula (IC) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of a disease where theinhibition of CRTh2 is beneficial:

in which:n represents 1 or 2;R¹ is one or more substituents independently selected from halogen, CN,nitro, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴,NR⁹CO₂R⁴, NR⁹COR⁴, aryl, heteroaryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₁₋₆alkyl, the latter five groups being optionally substituted by one ormore substituents independently selected from halogen, OR₇ and NR⁸R⁹,NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1 or 2;R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, COR⁴ or C₁₋₇alkyl, thelatter group being optionally substituted by one or more substituentsindependently selected from halogen atoms, OR⁸ and NR⁵R⁶, S(O)_(x)R⁷where x is 0, 1 or 2;R³ is aryl or a 5-7 membered or 6,6- or 6,5-fused bicyclic aromatic ringeach containing one or more heteroatoms selected from N, S and O, andeach of which is optionally substituted by one or more substituentsindependently selected from halogen, CN, nitro, SO₂R⁴, OH, OR⁴, SR⁴,SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl, the latter three groups beingoptionally substituted by one or more substituents independentlyselected from halogen atoms, OR⁷ and NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1or 2;R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl, all of which may beoptionally substituted by one or more substituents independentlyselected from halogen atoms, aryl, heteroaryl, OR¹⁰ andNR¹¹R¹²S(O)_(x)R¹³ (where x=0, 1 or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵,SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro;R⁵ and R⁶ independently represent a hydrogen atom, a C₁-C₆ alkyl group,an aryl, or a heteroaryl, the latter three of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, aryl, OR¹³ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵,SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro;orR⁵ and R⁶ together with the nitrogen atom to which they are attached canform a 3-8 membered saturated heterocylic ring optionally containing oneor more atoms selected from O, S(O)_(x) where x is 0, 1 or 2, NR¹⁶, andthe ring itself optionally substituted by C₁-C₃ alkyl;R⁷ and R¹³ independently represent a C₁-C₆ alkyl group, an aryl orheteroaryl group all of which may be optionally substituted by halogenatoms;R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionallysubstituted by halogen atoms, aryl or heteraryl groups, both of whichmay also be optionally substituted by one or more fluorine atoms); anaryl or a heteroaryl group, which may be optionally substituted by oneor more halogen atoms;each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a hydrogenatom, C₁-C₆ alkyl, an aryl or a heteroaryl group (all of which may beoptionally substituted by one or more halogen atoms); andR¹⁶ is hydrogen, C₁₋₄ alkyl, —C(O)C₁-C₄ alkyl, C(O)YC₁-C₄alkyl, Y is Oor NR⁷.

As used below, the term “compound of formula (I)” referes to anycompound above of formula (I), (IA), (IB) or (IC).

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The compound of formula (I) above may be converted to a pharmaceuticallyacceptable salt or solvate thereof, preferably a basic addition saltsuch as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc,benzathine, chloroprocaine, choline, diethanolamine, ethanolamine,ethyldiamine, meglumine, tromethamine or procaine, or an acid additionsalt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate. Preferred salts include sodium salts.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups in the startingreagents or intermediate compound may need to be protected by protectinggroups. Thus, the preparation of the compound of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups. The protection and deprotection of functional groups is fullydescribed in is ‘Protective Groups in Organic Chemistry’, edited by J.W. F. McOmie, Plenum Press (1973), and ‘Protective Groups in OrganicSynthesis’, 3rd edition, T. W. Greene & P. G. M. Wuts,Wiley-Interscience (1999).

Compounds of formula (I) can be prepared by:

(a) oxidation of a compound of formula (II):

in which R¹⁷ is hydrogen or alkyl and R¹, R² and R³ are as defined informula (I) or are protected derivatives thereof, or(b) reaction of a compound of formula (M):

in which R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof, with a compound of formula (IV):

L-C(O)OR¹⁸  (IV)

where R¹⁸ is an alkyl group and L is a leaving group in the presence ofa base, and optionally thereafter (a) or (b) in any order:

-   -   hydrolysing the ester group R¹⁷ or R¹⁸ to the corresponding acid    -   removing any protecting group    -   forming a pharmaceutically acceptable salt.

For process (a) suitable oxidising agents include MCPBA, H₂O₂ or oxone.When R¹⁷ is alkyl, ethyl, methyl or tertiary-butyl groups are preferred.Where R¹⁷ is hydrogen compounds of formula (I) are obtained directly byoptionally removing of a protecting group and formation of appropriatesalts.

Where R¹⁷ is alkyl the corresponding ester can be hydrolysed. Hydrolysisof the ester group R¹⁷ can be carried out using routine procedures, forexample by stirring with base, preferably aqueous sodium or lithiumhydroxide, or stirring with an acid such as TFA and optionally removingof protecting groups and formation of appropriate salts.

For process (b) the reaction can be carried out in a suitable solventsuch as THF using a base such as sodium hydride or the like. Suitablegroups R¹⁸ include C₁₋₆ alkyl groups such as methyl, ethyl ortertiary-butyl. Suitable L is a leaving group such as halo, inparticular bromo. Preferably the compound of formula (IV) is ethylbromoacetate.

Hydrolysis of the ester group R¹⁸ can be carried out using routineprocedures as described above for R¹⁷.

Compounds of formula (III) can be prepared by reaction of a compound offormula (V) using process (a):

in which R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof, with an oxidising agent, and optionally thereafterremoving any protecting group.

Compounds of formula (V) where R¹, R² and R³ are as defined in formula(I) or are protected derivatives thereof can be prepared by reacting acompound of formula (VI) with a compound of formula (VII):

in which R¹, R² and R³ are as defined in formula (I), or protectedderivatives thereof.

Preferably the reaction is carried out in acetic acid with heating.

Or, compounds of formula (V) where R¹, R² and R³ are as defined informula (I) or are protected derivatives thereof, can be prepared byreacting a compound of formula (VIII) with a compound of formula (VII):

Compounds of formula (VI), ((VII) and (VIII) are commercially availableor can be prepared using standard chemistry well known in the art. WhereR¹, R² and R³ are as defined in formula (I) or are protected derivativesthereof. Preferably the reaction is carried out in a suitable solvent,such as dichloromethane or THF in the presence of a chlorinating agentsuch as sulfonyl chloride or tertiary-butyl hypochlorite.

Alternatively compounds of formula (I) can be prepared by reactingcompounds of formula (IX) with compounds of formula (X). Where R¹, R²and R³ are as defined in formula (I) or are protected derivativesthereof.

Preferably the reaction is carried out in a suitable solvent such asethanol or DMF, in the presence of iodine.

Compounds of formula (IX) can be prepared by reaction of compounds offormula (XI) and (IV) as outlined above.

Compounds of formula (X) and (XI) are commercially available or can beprepared using standard chemistry well known in the art. Where R¹, R²and R³ are as defined in formula (I) or are protected derivativesthereof.

Compounds of formula (II) in which R¹ is aryl are prepared fromcompounds of formula (II) in which R¹ is halogen, preferably bromine oriodine using Suzuki coupling conditions, preferably usingtetrakistriphenylphosphine palladium (0) as a catalyst in a suitableorganic solvent, such as toluene, with heating.

Compounds of formula (II) in which R¹ is NR⁹SO₂R⁴ are prepared fromcompounds of formula (XII) by reacting with a suitable base, preferablysodium hydroxide.

Compounds of formula (XII) are prepared from compounds of formula (XIII)

Compounds of formula (XIII) are hydrogenated in the presence of asuitable catalyst such as platinum on charcoal, in acidic conditions.The product of this reaction is then reacted with a sulfonyl chloridecompound in the presence of a base, preferably triethylamine in anorganic solvent, such as acetonitrile.

Compounds of formula (XIII) are prepared from compounds of formula (II)in which R¹ is NO₂, by reaction with a suitable oxidising agent (processA).

Compounds of formula (I) in which R¹ is NRCOR are prepared byhydrogenation of a to compound of formula (II) in which R¹ is nitro, asoutlined for compounds of formula (XII) above. The reduced product isthen treated with an acyl chloride [ClC(O)R⁴] in the presence of base togive a compound of formula (II), this is subsequently hydrolysed andoxidised (processes a and b) to give a compound of formula (I) asoutlined previously.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of CRTh2 receptor activity, and may be used inthe treatment (therapeutic or prophylactic) of conditions/diseases inhuman and non-human animals which are exacerbated or caused by excessiveor unregulated production of PGD₂ and its metabolites. Examples of suchconditions/diseases include:

-   -   (1) (the respiratory tract) obstructive airways diseases        including: asthma (such as bronchial, allergic, intrinsic,        extrinsic and dust asthma particularly chronic or inveterate        asthma (e.g. late asthma and airways hyper-responsiveness));        chronic obstructive pulmonary disease (COPD)(such as        irreversible COPD); bronchitis (including eosinophilic        bronchitis); acute; allergic, atrophic rhinitis or chronic        rhinitis (such as rhinitis caseosa, hypertrophic rhinitis,        rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa,        membranous rhinitis (including croupous, fibrinous and        pseudomembranous rhinitis), scrofoulous rhinitis, perennial        allergic rhinitis, easonal rhinitis (including rhinitis nervosa        (hay fever) and vasomotor rhinitis); nasal polyposis;        sarcoidosis; farmer's lung and related diseases; fibroid lung;        idiopathic interstitial pneumonia; cystic fibrosis; antitussive        activity; treatment of chronic cough associated with        inflammation or iatrogenic induced;    -   (2) (bone and joints) arthrides including rheumatic, infectious,        autoimmune, seronegative, spondyloarthropathies (such as        ankylosing spondylitis, psoriatic arthritis and Reiter's        disease), Behcet's disease, Sjogren's syndrome and systemic        sclerosis;    -   (3) (skin and eyes) psoriasis, atopical dermatitis, contact        dermatitis, other eczmatous dermitides, seborrhoetic dermatitis,        Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis        bullosa, urticaria, angiodermas, vasculitides, erythemas,        cutaneous eosinophilias, chronic skin ulcers, uveitis, Alopecia        greatacorneal ulcer and vernal conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, irritable bowel disease; food-related        allergies which have effects remote from the gut, (such as        migraine, rhinitis and eczema);    -   (5) (central and peripheral nervous system) Neurodegenerative        diseases and dementia disorders (such as Alzheimer's disease,        amyotrophic lateral sclerosis and other motor neuron diseases,        Creutzfeldt-Jacob's disease and other prion diseases, HIV        encephalopathy (AIDS dementia complex), Huntington's disease,        frontotemporal dementia, Lewy body dementia and vascular        dementia), polyneuropathies (such as Guillain-Barré syndrome,        chronic inflammatory demyelinating polyradiculoneuropathy,        multifocal motor neuropathy), plexopathies, CNS demyelination        (such as multiple sclerosis, acute disseminated/haemorrhagic        encephalomyelitis, and subacute sclerosing panencephalitis),        neuromuscular disorders (such as myasthenia gravis and        Lambert-Eaton syndrome), spinal diorders (such as tropical        spastic paraparesis, and stiff-man syndrome), paraneoplastic        syndromes (such as cerebellar degeneration and        encephalomyelitis), CNS trauma, migraine and stroke.    -   (6) (other tissues and systemic disease) atherosclerosis,        Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus;        systemic lupus, erythematosus; Hashimoto's thyroiditis, type I        diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE        syndrome, lepromatous leprosy, idiopathic thrombocytopenia        pupura; post-operative adhesions, sepsis and        ischemic/reperfusion injury in the heart, brain, peripheral        limbs hepatitis (alcoholic, steatohepatitis and chronic viral),        glomerulonephritis, renal impairment, chronic renal failure and        other organs    -   (7) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (8) Diseases associated with raised levels of PGD₂ or its        metabolites.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CRTh2 receptor subfamily.

Particular conditions which can be treated with the compounds of theinvention are asthma, rhinitis and other diseases in which raised levelsof PGD₂ or its metabolites. It is preferred that the compounds of theinvention are used to treat asthma.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the to manufacture of amedicament for use in therapy.

In a further aspect, the present invention provides the use of acompound or formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy in combination with drugs used to treatasthma and rhinitis (such as inhaled and oral steroids, inhaledO₂-receptor agonists and oral leukotriene receptor antagonists).

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof; as hereinbefore defined in the manufacture of amedicament for the treatment of human diseases or conditions in whichmodulation of CRTh2 receptor activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating diseasesmediated by PGD2 or its metabolites wherein the prostanoid binds to itsreceptor (especially CRTh2) receptor, which comprises administering to apatient a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt, solvate or prodrug thereof; ashereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate or prodrug thereof, ashereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compound of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as herein before defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Preferably the compound of the invention isadministered orally.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) the title and sub-titled compounds of the examples and methods werenamed using the ACD labs/name program (version 6.0) from AdvancedChemical Development Inc, Canada;(ii) unless stated otherwise, reverse phase preparative HPLC wasconducted using a Symmetry, NovaPak or Ex-Terra reverse phase silicacolumn;(iii) Flash column chromatography refers to normal phase silicachromatography to (iv) solvents were dried with MgSO₄ or Na₂SO₄(v) Evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;(vi) Unless otherwise stated, operations were carried out at ambienttemperature, that is in the range 18-25° C. and under an atmosphere ofan inert gas such as argon or nitrogen;(vii) yields are given for illustration only and are not necessarily themaximum attainable;(viii) the structures of the end-products of the formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;(ix) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMRanalysis;(x) mass spectra (MS): generally only ions which indicate the parentmass are reported when given, ¹H NMR data is quoted in the form of deltavalues for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as an internal standard;(xi) the following abbreviations are used:

-   -   EtOAc Ethylacetate    -   DMF N,N-Dimethyl formamide    -   NMP N-methylpyrrolidine    -   THF tetrahydrofuran    -   RT room temperature    -   trifluoroacetic acid    -   MCPBA meta-chloroperbenzoic acid

EXAMPLE 1 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

(a) 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole

To a solution of methylphenylhydrazine (7 g) in acetonitrile (100 ml)was added 1-[(4-chlorophenyl)thio]acetone (8.84 g) and water (10 ml).The mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and the residue dissolved indichloromethane. The solution was washed with sodium hydrogen carbonate,brine, dried (MgSO₄) and concentrated in vacuo. The residue wasrecrystallised (methanol) to give the sub-title compound (6 g).

MS: APCI+ [M+H] 288

(b) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole

The product of example 1 step (a) (1.85 g) was dissolved indichloromethane (20 ml) at 0° C., to this solution MCPBA (2.85 g) wasadded and stirred for 2 hours. The reaction mixture was then washed withsodium carbonate solution, the organic extracts were dried with MgSO₄.Purification by Flash column chromatography (35% EtOAc/hexane as eluent)gave of the sub-title compound (1.27 g).

MS: ES+ [M+H] 320

(c) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid,ethyl ester

The product of step (b) (1.27 g) was dissolved in THF (20 ml) at ° C.and NaH (0.115 g, 60% dispersion in oil) was added and stirred for 30min. Ethylbromoacetate (0.66 ml) was then added and stirred for 1 h atroom temperature. Ethanol was added to quench the reaction, the solventwas removed and the product washed with water and extracted with EtOAc.Purification by Flash column chromatography (30% EtOAc/hexane as eluent)gave the sub-title compound (0.716 g).

MS: ES+[M+H] 406

(d) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid

The product of step (c) was dissolved in ethanol (10 ml) and 10% NaOH(aq) (10 ml) was added and stirred for 1 h. The reaction mixture wasthen acidified with HCl (aq), and extracted with EtOAc. Purification bysolid phase extraction using NH₂ sorbent (2 g), eluting withacetonitrile followed by 10% acetic acid/acetonitrile, gave the titlecompound (0.301 g).

MS: ES− [M−H] 376

¹H NMR (DMSO) δ 2.42 (3H, s), 2.62 (3H, s), 4.68 (2H, s), 7.01 (1H, dd),7.29-7.33 (1H, m), 7.58-7.62 (2H, m), 7.65-7.69 (1H, m), 7.87-7.93 (2H,m).

EXAMPLE 25-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acida) 5-chloro-3-[4(-chlorophenyl)sulfonyl]-2-methyl-1H-indole

To a suspension of (4-chlorophenyl)-hydrazine hydrochloride (2 g) inacetic acid (30 ml) was added 1-[(4-chlorophenyl)thio]-acetone (2.24 g),acetonitrile (20 ml) and water (10 ml). The mixture was strirred at roomtemperature overnight. The reaction mixture was concentrated in vacuoand the residue suspended in EtOAc, washed with sodium hydrogencarbonate solution, brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in acetic acid (20 ml) and heated to 80° C.overnight. The reaction mixture was poured into water, basified usingNaOH and the organics extracted into EtOAc. The EtOAc was washed withbrine, dried (MgSO₄) and concentrated in vacuo. Purification by Flashcolumn chromatography (20% EtOAc/hexane as eluent) gave the sub-titlecompound (2.2 g).

¹H NMR (CDCl₃) δ 8.31 (1H, s), 7.48 (1H, d), 7.26 (2H, m), 7.13 (3H, m),6.93 (2H, m), 2.51 (3H, s).

b) 5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,methyl ester

To a solution of the product of step (a) (0.2 g) in THF (5 ml) was added1M sodium bis(trimethylsilyl)amide solution in THF (0.65 ml). Themixture was stirred for 30 min before bromo-acetic acid, methyl ester(62 μl) was added, the reaction was stirred at room temperatureovernight. A further 0.3 ml of 1.0M sodium bis(trimethylsilyl)amidesolution in THF and 30 μl of methyl bromoacetate was added to themixture and was stirred for a further 3 h. The mixture was then adsorbedonto silica and purified by Flash column chromatography (14%EtOAc/hexane as eluent) to give sub-title compound (0.21 g).

¹H NMR (CDCl₃) d 7.52 (1H, d), 7.27 (1H, d), 7.20-7.10 (3H, m),6.97-6.89 (2H, m), 4.80 (2H, d), 3.79 (3H, d), 2.47 (3H, d).

c) 5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, methyl ester

To a solution of the product of step (b) (0.1 g) in dichloromethane (5ml) was added MCPBA (121 mg). The mixture was stirred at roomtemperature overnight. The reaction was diluted with dichloromethane (10ml), washed with sodium hydrogen carbonate solution, brine, dried(MgSO₄) and concentrated in vacuo to give sub-title compound (0.1 g).Used in step (d) without further purification and characterisation.

d) 5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

To a solution of the product from step (c) (0.09 g) in THF (5 ml) wasadded a 1.25 M solution of NaOH(aq) (0.25 ml). The reaction was stirredovernight at room temperature. The reaction mixture was concentrated invacuo and the residue dissolved/suspended in water. The pH was adjustedto 2 using dilute HCl (aq) and the solid which precipitated was isolatedby filtration, dried under vacuum at 40° C. to give the title compound.

MS: APCI−[M−H] 398

¹H NMR (DMSO) δ 7.94 (2H, m), 7.89 (1H, d), 7.67-7.62 (3H, m), 7.29 (1H,m), 5.12 (2H, s), 2.63 (3H, s).

EXAMPLE 36-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acida) 6-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole

The subtitle compound was prepared by the method of example 2 part (a)using (3-chlorophenyl)-hydtazine hydrochloride. Product purified usingFlash column chromatography (10% EtOAc/hexane as eluent).

¹H NMR (CDCl₃) δ 8.27 (1H, s) 7.39 (1H, d) 7.34 (1H, d), 7.10 (3H, m),6.92 (2H, m), 2.50 (3H, s).

b) 6-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,methyl ester

The sub-title compound was prepared by the method of example 2 part (b)using the product from part (a). ¹H NMR (CDCl₃) δ 7.43 (1H, d),7.27-7.25 (1H, m), 7.14-7.09 (3H, m), 6.92 (2H, dd), 4.85 (2H, s), 3.80(3H, d), 2.46 (3H, d).

c) 6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, methyl ester

The sub-title compound was prepared by the method of example 2 part (c)using the product from part (b). Used in step (d) without furtherpurification or characterisation.

d) 6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the product from part (c).

MS: ES− [M−H] 398

¹H NMR (DMSO) δ 7.94-7.89 (3H, m), 7.80 (1H, d) 7.64 (2H, m), 7.27 (1H,m), 5.13 (2H, s), 2.63 (3H, s).

EXAMPLE 47-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acida) 7-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole

The subtitle compound was prepared by the method of example 2 part (a)using (2-chlorophenyl)-hydrazine hydrochloride. ¹H NMR (CDCl₃) δ 8.48(1H, s) 7.40 (1H, d), 7.19 (1H, m) 7.13-7.11 (2H, m), 7.06 (1H, t),6.96-6.92 (2H, m), 2.55 (3H, s).

b) 7-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,methyl ester

The sub-title compound was prepared by the method of example 2 part (b)using the product from step (a).

¹H NMR (CDCl₃) δ 7.44 (1H, d), 7.18-7.09 (3H, m), 7.03 (1H, td), 6.92(2H, dd), 5.37 (2H, d), 3.81 (3H, d), 2.46 (3H, d).

c) 7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, methyl ester

The sub-title compound was prepared by the method of example 2 part (c)using the product from step (b). Used in step (d) without furtherpurification or characterisation.

d) 7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the product from part (c).

MS: ES− [M−H] 398

¹H NMR (DMSO) δ 7.96-7.93 (3H, m), 7.65 (2H, m), 7.30 (1H, m), 7.22 (1H,t) 5.32 (2H, s), 2.70 (3H, s).

EXAMPLE 55-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-4H-indole-1-aceticacid a) 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-4-carbonitrile

A stirred solution of 1-[(4-chlorophenyl)thio]-acetone (6.14 g) in drydichloromethane (150 ml) at −78° C. was treated with sulphuryl chloride(2.25 ml). After 30 min a prepared solution ofN,N,N′,N′-tetramethyl-1,8-naphthalenediamine (6.01 g) and5-amino-2-chloro-benzonitrile (3.89 g) in dry dicholoromethane (80 ml)was added dropwise over 30 min. The mixture was stirred for a further 2h, after which triethylamine (4.26 ml) was added and the reactionallowed to reach room temperature. The reaction mixture was diluted withdichloromethane (200 ml), washed with water, 1N HCl and brine. Theorganic phase was dried (MgSO₄), evaporated in vacuo, and the residuepurified by flash column chromatography eluting with iso-hexane andethyl acetate (1:1) to give the sub-title compound (1 g), and theregioisomer (600 mg) used in example 6 below.

¹H NMR CDCl₃: δ 12.52 (s, 1H), 7.74 (d, 1H), 7.38 (dd, 1H), 7.29 (m,2H), 6.97 (m, 2H), 3.29 (s, 3H).

b) 3-[(4-chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-aceticacid, methyl ester

The sub-title compound was prepared by the method of example 1 part (c)using the product of part (a).

¹H NMR CDCl₃: δ 7.37 (1H, d), 7.30 (1H, d), 7.18-7.13 (2H, m), 7.00-6.96(2H, m), 4.92 (2H, m), 3.80 (3H, m), 2.55 (3H, s).

c)5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-aceticacid, methyl ester

The sub-title compound was prepared by the method if example 1 part (b)from the product of part (b).

(d)5-Chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 1 part (d)using the product of part (c).

¹H NMR DMSO: δ 2.81 (3H, s), 5.29 (2H, s), 7.62 (1H, s), 7.7 (2H, m),7.98 (2H, m) and 8.08 (1H, d).

MS: APCI+ [M+H] 422

EXAMPLE 65-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-aceticacid a)5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-6-carbonitrile

Obtained from example 5 part (a)

¹H NMR CDCl₃: δ 8.68 (1H, s), 7.69 (1H, s), 7.61 (1H, s), 7.15 (2H, dt),6.91 (2H, dt), 2.57 (3H, s).

b)5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-aceticacid

Prepared by the method of example 2 part (d) to give the title compoundas a white solid.

¹H NMR DMSO: δ 8.42 (1H, s), 7.59 (1H, s), 7.3 (2H, dt), 6.99 (2H, dt),5.24 (2H, s), 2.46 (3H, s).

M.pt 256-258° C.

MS: APCI [M−H] 389

EXAMPLE 7 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-aceticacid a) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-aceticacid, ethyl ester

MCPBA (1.07 g) was added to a solution of example 1 part a) (1.79 g) indichloromethane (20 ml) at 0° C. The reaction mixture was stirred for 1h, after which further mCPBA (53 mg) was added and stirred for a further30 min. The reaction mixture was allowed to reach room temperature andthe sub-title compound was obtained as a white solid after filtration(0.68 g). Used directly in the next step without further purification.

b) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid

NaH (0.13 g, 60% dispersion in mineral oil) was added to the productfrom part (a) (0.685 g) in THF at 0° C. The reaction mixture was stirredfor 30 min and then ethyl bromoacetate (0.26 ml) was added and themixture stirred for 1 h. Ethanol was added and then concentrated invacuo. The product was extracted with EtOAc, dried (MgSO₄) andconcentrated in vacuo to give a white solid (761 mg). The solid wasdissolved in ethanol (15 ml), NaOH (10% solution, 5 ml) and then thesolution stirred overnight. The reaction mixture was acidified (diluteHCl) and extracted with EtOAC. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The product was purified with amine resin,eluting with MeCN and then 5% acetic acid in MeCN to give the titlecompound (60 mg).

¹H NMR DMSO: δ 7.61 (4H, s), 7.2-7.25 (1H, m), 6.88-6.91 (1H, m),6.88-6.86 (1H, m), 4.43 (2H, s), 2.57 (3H, s) and 2.21 (3H, s).

EXAMPLE 83-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-4H-indole-1-aceticacid a)3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole

Prepared by the method of example 5 part (a) from5-(ethylsulfonyl)-2-methoxy-benzenamine.

¹H NMR CDCl₃: δ 9.00 (1H, s), 7.91 (1H, d), 7.12 (2H, dd), 6.86 (2H, m),6.73 (1H, d), 4.05 (3H, s), 3.46 (2H, q), 2.46 (3H, s) and 1.16 (3H, t).

b)3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-aceticacid, methyl ester

Prepared by the method of example 5 part (b), using the product of sterp(a.)

¹H NMR CDCl₃: δ 7.92 (1H, d), 7.13 (2H, dt), 6.85 (2H, dt), 6.73 (1H,d), 5.27 (2H, s), 3.98 (3H, s), 3.79 (3H, s), 3.48 (2H, q), 2.38 (3H, s)and 1.18 (3H, t).

c)3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-aceticacid, methyl ester

Prepared by the method of example 5 part (c) using the product of step(b).

MS: ES+ [M+H] 435

d)3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-aceticacid

Prepared by the method of example 5 part (d) using the product of step(c).

¹H NMR DMSO: δ 7.79 (1H, d), 7.73 (2H, d), 7.58 (2H, d), 7.04 (1H, d),5.07 (2H, s), 3.95 (3H, s), 3.58 (2H, q), 2.66 (3H, s) and 1.23 (3H, t).

EXAMPLE 93-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-acetic acid a)3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole

To a stirred solution of 4-aminobenzonitrile (5 g) in dichloromethane(150 ml) cooled to −70° C. was added t-butyl hypochlorite (4.6 g)dropwise over 5 mins. The reaction was stirred for 10 mins before1-[4-chlorophenyl)thio]-2-propanone (8.49 g) was added as a solution indichloromethane (20 ml). After 1 h triethylamine (5.9 ml) was added andthe reaction allowed to warm to room temperature. The reaction wasdiluted with dichloromethane, washed with HCl (aq), brine, dried overMgSO₄, and concentrated in vacuo to give a brown solid. Purification byrecystallisation from Methanol gave the subtitle compound (7.5 g).

¹H NMR (CDCl₃) δ 8.61 (s, 1H), 7.84 (s, 1H), 7.44 (dd, 1H), 7.41 (d,1H), 7.19-7.08 (m, 2H), 6.93 (dd, 2H), 2.56 (s, 3H).

b) 3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-acetic acid,ethyl ester

The subtitle compound was prepared by the method of example 5 part (b)using the product from part (a) and ethyl bromoacetate. The product wasused without further characterisation in part (c).

c) 3-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-aceticacid, methyl ester

mCPBA (128 mg) was added to the product of part (b) (200 mg) indichloromethane (10 ml), and stirred overnight. The solution was washed(NaHCO₃), brine, then dried (MgSO₄) and concentrated in vacuo to givethe subtitle compound as a white solid (170 mg).

d) 3-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-acetic acid

The title compound was prepared by the method of example 5 part (d)using the product of step (c).

¹H NMR (DMSO) δ 7.69-7.57 (m, 6H), 7.51 (dd, 1H), 4.85 (dd, 2H) and 2.63(s, 3H)

EXAMPLE 103-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic acid a)1H-indole-1-acetic acid,3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic acid,methyl ester

The sub-title compound was prepared by the method of example 5 part (c)using the product of example 9 part (b).

¹H NMR (DMSO) δ 8.35 (d, 1H), 8.03 (dt, 2H), 7.82 (d, 1H), 7.71-7.62 (m,3H), 5.32 (s, 2H), 4.15 (q, 2H), 2.67 (s, 3H) and 1.18 (td, 3H)

b) 1H-indole-1-acetic acid,3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic acid

The title compound was prepared by the method of example 5 part (d)using the product of step (a)

¹H NMR (DMSO) δ 8.35 (d, 1H), 8.05-8.01 (m, 2H), 7.82 (d, 1H), 7.69-7.63(m, 3H), 5.20 (s, 2H) and 2.67 (s, 3H).

EXAMPLE 11 Sodium5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetate

Sodium hydroxide (1M, 4.3 ml) was added to a solution of the product ofexample 1 part (c) (1.75 g) in THF (60 ml). The reaction mixture wasstirred overnight and then concentrated in vacuo. The residue wasrecrystallised from water to give the title compound as a white solid.

¹H NMR (DMSO) δ 7.89 (dd, 2H), 7.66 (d, 1H), 7.61 (m, 2H), 7.26 (d,1H.), 6.99 (1H, dd), 4.39 (s, 2H), 2.59 (s, 3H) and 2.4 (s, 3H).

EXAMPLE 124-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid

a) 4-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole

The subtitle compound was prepared by the method of example 2 part (a)using (3-chlorophenyl)-hydrazine hydrochloride. Product purified usingFlash column chromatography (10% EtOAc/hexane as eluent).

¹H NMR (CDCl₃) δ 8.38 (1H, s), 7.27-7.24 (2H, m), 7.15-7.11 (2H, m),7.09-7.08 (1H, m), 6.96 (2H, dt), 2.52 (3H, s)

b) 4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole

The subtitle compound was prepared by the method of example 1 part (b)using the product from part (a). Product was purified using Flash columnchromatography (33% EtOAc/hexane as eluent). ¹H NMR (DMSO) δ 12.57 (1H,s), 7.83 (2H, dt), 7.60 (2H, dt), 7.41 (1H, dd), 7.18-7.08 (2H, m), 2.80(3H, s)

c) 4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The subtitle compound was prepared by the method of example 1 part (c)using the product from part (b). Product was purified using Flash columnchromatography (33% EtOAc/hexane as eluent).

¹H NMR (DMSO) δ 7.80 (2H, dt), 7.63 (3H, m), 7.25-7.16 (2H, m), 5.36(2H, s), 4.20, (2H, q), 2.81 (3H, s), 1.23 (3H, t).

d) 4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the product from part (c). Product was purified using reversephase preparative HPLC (eluent MeCN/NH₃(aq)).

¹H NMR (DMSO) δ 7.79 (2H, dt), 7.62 (2H, dt), 7.52 (1H, dd), 7.19-7.11(2H, m), 4.84 (2H, s), 2.78 (3H, s).

APCI− (M−H) 395.

EXAMPLE 13 3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

a) 2,5-dimethyl-1H-indol-1-acetic acid

60% sodium hydride/oil (0.64 g) was added to a solution of2,5-dimethyl-1H-indole (2.0 g) in DMF (15 ml). After 15 min ethylbromoacetate (2.7 ml) was added quickly and the reaction stirred for 20min. The mixture was quenched with 1% aqueous acetic acid (100 ml),extracted with ethyl acetate (2×100 ml) and washed with water (2×50 ml)and brine (20 ml). The extracts were dried (MgSO₄), filtered andevaporated in vacuo to yield a brown solid. The solid was dissolved inEtOH (20 ml) and aqueous sodium hydroxide (1M, 10 ml) added. After 1 hthe solution was adjusted to pH6 with aqueous hydrochloric acid (1M, ˜10ml), and then evaporated in vacuo. The residue was purified by flashcolumn chromatography (gradient 1-10% methanol in dichloromethane). Thesub-title compound was obtained as a red/brown solid (1.3 g).

MS: APCI+ [M+H] 204

¹H NMR δ_((DMSO)) 7.22-7.17 (2H, m), 6.85 (1H, d), 6.11 (1H, s), 4.87(2H, s), 2.34 (3H, s), 2.30 (3H, s)

b) 3-[(4-methoxyphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid,ammonium salt

Iodine (0.51 g) was added to a solution of 4-methoxylbenzenethiol (0.25g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After1 h the solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo and the oily residue treated with ether to give asolid. Filtered off and dried to yield the title compound as a whitesolid (0.27 g).

MS (APCI−) 340 [(M−NH₄)—H]⁻

¹H NMR δ_((DMSO)) 7.24 (1H, d), 7.15 (1H, s), 6.95 (2H, d), 6.90 (1H,d), 6.78 (2H, d), 4.60 (2H, s), 3.66 (3H, s), 2.38 (3H, s), 2.33 (3H, s)

c) 3-[(4-methoxyphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.44 g) was added to a solution ofthe product from example 13 step ii) (0.2 g) in acetonitrile (4 ml). Thereaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml)added and stirred for a further 15 min. The mixture was filtered,purified by reverse phase HPLC and evaporated in vacuo to yield thetitle compound as a white solid (98 mg).

MS: APCI− [M−H] 372

¹H NMR δ_((DMSO)) 7.83 (2H, d), 7.69 (1H, s), 7.33 (1H, d), 7.09-6.98(1H, m), 7.06 (2H, d), 4.79 (3H, s), 3.78 (3H, s), 2.59 (3H, s), 2.40(3H, s)

EXAMPLE 14 3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

a) 3-[(3-methoxyphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid

Iodine (0.51 g) was added to a solution of 3-methoxylbenzenethiol (0.25g) and the product from example 13 step i) (0.2 g) in DMF (5 ml). After1 h the solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo and the oily residue treated with ether to give asolid. Filtered off and dried to yield the title compound as a whitesolid (0.22 g).

MS: APCI− [M−H] 340

¹H NMR δ_((DMSO)) 7.40 (1H, d), 7.16 (1H, s), 7.11 (1H, t), 6.98 (1H,d), 6.63 (1H, d), 6.55 (1H, d), 6.45 (1H, s), 5.08 (2H, s), 3.61 (3H,s), 2.39 (3H, s), 2.34 (3H, s)

b) 3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.4 g) was added to a solution of theproduct from example 14 step i) (0.18 g) in acetonitrile (4 ml). Thereaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml)added and stirred for a further 15 min. The mixture was filtered,purified by reverse phase HPLC and evaporated in vacuo to yield thetitle compound as a white solid (70 mg).

MS: APCI− [M−H] 372

¹H NMR δ_((DMSO)) 7.69 (1H, s), 7.48-7.43 (2H, m), 7.36-7.32 (1H, m),7.31 (1H, d), 7.18-7.11 (1H, m), 7.01 (1H, d), 4.66 (2H, s), 3.78 (3H,s), 2.61 (3H, s), 2.40 (3H, s)

EXAMPLE 15 3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

a) 3-[(2-Chlorophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid, sodiumsalt

Iodine (0.22 g) was added to a solution of 2-chlorobenzenethiol (0.13 g)and the product from example 13 step a) (015 g) in EtOH (5 ml). After 1h the solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo to yield the product as a colourless oil. The oilwas then dissolved in MeOH (10 ml) treated with aqueous sodium hydroxide(1M, 0.52 ml) and evaporated in vacuo to yield the sodium salt as awhite solid (0.13 g).

MS: APCI− [M−Na] 344

¹H NMR δ_((DMSO)) 7.28-7.15 (2H, m), 7.13-7.06 (2H, m), 6.97-6.88 (3H,m), 4.42 (2H, s), 2.36 (3H, s), 2.33 (3H, s)

b) 3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.14 g) was added to a solution ofthe product from example 15 step a) (0.07 g) in acetonitrile (2 ml) andwater (0.5 ml). The reaction was stirred for 1 h, 1M aqueous sodiumthiosulphate (2 ml) added and stirred for a further 15 min. The mixturewas filtered, purified by reverse phase HPLC and evaporated in vacuo toyield the title compound as a white solid (11 mg).

MS APCI− [M−H] 376

¹H NMR δ_((DMSO)) 8.32-8.25 (1H, m), 7.64-7.52 (3H, m), 7.39 (1H, s),7.34 (1H, d), 6.99 (1H, d), 4.73 (2H, s), 2.59 (3H, s), 2.32 (3H, s)

EXAMPLE 16 3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

a) 3-[(3-Chlorophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid, sodiumsalt

Iodine (0.29 g) was added to a solution of 3-chlorobenzenethiol (0.175g) and the product from example 13 step a) (0.2 g) in EtOH (5 ml). After1 h the solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo to yield the product as a colourless oil. The oilwas then dissolved in MeOH (10 ml) treated with aqueous sodium hydroxide(1M, 0.52 ml) and evaporated in vacuo to yield the sodium salt as awhite solid (0.19 g).

MS (APCI−) 344 [(M−Na)−H]⁻

¹H NMR δ^((DMSO)) 7.28-7.15 (2H, m), 7.13-7.06 (2H, m), 6.97-6.88 (3H,m), 4.42 (2H, s), 2.36 (3H, s), 2.33 (3H, s)

b) 3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a solution ofthe product from is example 16 step a) (0.16 g) in acetonitrile (4 ml)and water (1 ml). The reaction was stirred for 1 h, 1M aqueous sodiumthiosulphate (2 ml) added and stirred for a further 15 min. The mixturewas filtered, purified by reverse phase HPLC and evaporated in vacuo toyield the title compound as a white solid (65 mg).

MS APCI−[M−H]⁻ 376

¹H NMR δ_((DMSO)) 7.87 (2H, d), 7.68 (2H, d), 7.63-7.56 (1H, m), 7.36(1H, d), 7.04 (1H, d), 4.79 (2H, s), 2.62 (3H, s), 2.41 (3H, s)

EXAMPLE 17 3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-aceticacid

a) 3-[(4-Cyanophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid, ammoniumsalt

Iodine (0.51 g) was added to a solution of 4-cyanobenzenethiol (0.27 g)and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 hthe solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo and the oily residue treated with ether to give asolid. Filtered off and dried to yield the title compound as a whitesolid (0.25 g).

MS APCI−[(M−NH₄)−H]⁻ 334

¹H NMR δ_((DMSO)) 7.62 (2H, d), 7.35 (1H, d), 7.10 (1H, s), 7.08 (2H,d), 6.97 (1H, d), 4.80 (2H, s), 2.36 (3H, s), 2.32 (3H, s)

b) 3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.44 g) was added to a solution ofthe product from example 17 step a) (0.21 g) in acetonitrile (4 ml). Thereaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml)added and stirred for a further 15 min. The mixture was filtered,purified by reverse phase HPLC and evaporated in vacuo to yield thetitle compound as a white solid (58 mg).

MS (APCI−) [M−H]⁻ 367

¹H NMR δ_((DMSO)) 8.04 (4H, dd), 7.69 (1H, s), 7.36 (1H, d), 7.04 (1H,d), 4.76 (2H, s), 2.61 (3H, s), 2.41 (3H, s)

EXAMPLE 18 3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-aceticacid

a) 3-[(2-methylphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid,ammonium salt

Iodine (0.29 g) was added to a solution of 2-methylbenzenethiol (0.16 g)and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 hthe solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo and the oily residue treated with ether to give asolid. Filtered off and dried to yield the title compound as a whitesolid (0.19 g).

MS APCI− [(M—NH₄)—H]⁻ 324

¹H NMR δ_((DMSO)) 7.24 (1H, d), 7.15 (1H, d), 7.07 (1H, s), 6.97-6.86(3H, m), 6.47 (1H, d), 4.49 (2H, s), 2.42 (3H, s), 2.33 (3H, s), 2.31(3H, s)

b) 3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a solution ofthe product from example 18 step a) (0.14 g) in acetonitrile (4 ml). Thereaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml)added and stirred for a further 15 min. The mixture was filtered,purified by reverse phase HPLC and evaporated in vacuo to yield thetitle compound as a white solid (65 mg).

MS APCI− [M−H]− 356

¹H NMR δ_((DMSO)) 8.05 (1H, d), 7.54-7.40 (2H, m), 7.44 (1H, s), 7.40(1H, d), 7.31 (1H, d), 7.01 (1H, d), 4.94 (2H, s), 2.54 (3H, s), 2.38(3H, s), 2.33 (3H, s)

EXAMPLE 19 3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-aceticacid

a) 3-[(2-ethylphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid, ammoniumsalt

Iodine (0.44 g) was added to a solution of 2-ethylbenzenethiol (0.32 g)and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 hthe solution was purified by reverse phase HPLC. The solvent wasevaporated in vacuo and the oily residue treated with ether to give asolid. Filtered off and dried to yield the title compound as a whitesolid (0.18 g).

MS (APCI−) 338 [(M—NH₄)—H]⁻

¹H NMR δ_((DMSO)) 7.26 (1H, d), 7.16 (1H, d), 7.08 (1H, s), 7.01-6.85(3H, m), 6.48 (1H, d), to 4.57 (2H, s), 2.83 (2H, q), 2.34 (3H, s), 2.31(3H, s), 1.31 (3H, t)

b) 3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a solution ofthe product from example 19 step a) (0.14 g) in acetonitrile (4 ml). Thereaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml)added and stirred for a further 15 min. The mixture was filtered,purified by reverse phase HPLC and evaporated in vacuo to yield thetitle compound as a white solid (45 mg).

MS APCI− [M−H]− 370

¹H NMR δ_((DMSO)) 7.95 (1H, d), 7.58-7.50 (1H, m), 7.47 (1H, s),7.44-7.34 (3H, m), 7.00 (1H, d), 4.81 (2H, s), 2.87 (2H, q), 2.51 (3H,s), 2.33 (3H, s), 0.94 (3H, t)

EXAMPLE 203-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic acid

a) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole

To a stirred solution of 3-nitroaniline (8 g) in THF (700 ml) cooled to−78° C. was added t-butyl hypochlorite (6.3 g) dropwise over 5 minutes.The reaction was allowed to warm to −65° C. over 20 minutes before1-[4-chlorophenyl)thio]-2-propanone (11.6 g) was added as a solution intetrahydrofuran (20 ml). After 2 hours triethylamine (8.1 ml) was addedand the reaction allowed to warm to room temperature. 2M HCl(aq) wasadded to the reaction mixture before concentration in vacuo. The residuewas slurried in methanol and the solid which precipitated isolated byfiltration to give the subtitle compound (5.8 g).

¹H NMR (DMSO)

12.55 (s; 1H), 7.76 (dd, 1H), 7.63 (dd, 1H), 7.31-7.22 (m, 3H), 6.91(dd, 2H), 2.47 (s, 3H)

b) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-acetic acid,ethyl ester

To a stirred suspension of sodium hydride, 60% dispersion in mineraloil, (0.85 g) in THF (100 ml) was added the product from part (a) (5.6g) as a solution in THF (50 ml). After stirring at room temperature for30 minutes ethyl bromoacetate (2.3 ml) was added dropwise over 10minutes. After 2 hours the reaction was concentrated in vacuo, theresidue dissolved in ethyl acetate, washed with water, brine, dried(MgSO₄) and concentrated in vacuo. Recrystallisation from boilingethanol gave the subtitle compound (5 g).

¹H NMR (DMSO)

7.97 (dd, 1H), 7.65 (dd, 1H), 7.35 (t, 1H), 7.26 (dt, 2H), 6.92 (dt,2H), 5.40 (s, 2H), 4.19 (q, 2H), 2.45 (s, 3H), 1.22 (t, 3H).

c) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-acetic acid,ethyl ester

To a solution of the product from part (b) (0.2 g) in dichloromethane(10 ml) was added MCPBA (0.245 g). After string overnight a further 20ml of dichloromethane was added to the reaction before the mixture waswashed with sodium hydrogen carbonate solution, brine, dried (MgSO₄) andconcentrated in vacuo. The residue was used without furthercharacterisation in step (d).

d) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-acetic acid

The title compound was prepared by the method of example 2 part (d)using the product from part (c). Product was purified using reversephase preparative HPLC (eluent MeCN/NH₃(aq)).

¹H NMR (DMSO)

7.97 (1H, dd), 7.85 (2H, dt), 7.68 (2H, m), 7.65 (1H, d), 7.40 (1H, t),5.10 (2H, s), 2.77 (3H, s). APCI− (M−H) 407

EXAMPLE 214-(Acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

a) 4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,ethyl ester

A suspension of the product from example 20 part (b) (2.25 g) in ethanol(170 ml) was stirred in the presence of 5% Pt/C (0.5 g) under 2 barpressure of H₂. After stirring overnight the catalyst was removed byfiltration and the filtrates concentrated in vacuo. Purification byflash column chromatography (14% EtOAc/hexane as eluent) gave thesubtitle compound (1.4 g).

¹H NMR (DMSO) δ 7.30 (dd, 2H), 7.0 (dt, 2H), 6.85 (t, 1H), 6.68 (dd,1H), 6.23 (dd, 1H), 5.33 (s, 2H), 5.09 (s, 2H), 4.16 (q, 2H), 2.33 (s,3H), 1.21 (t, 3H).

3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid, ethyl ester was also isolated as a by product from the reaction(0.33 g).

¹H NMR (DMSO) δ 7.32 (dd, 2H), 7.01 (dd, 2H), 6.95 (t, 1H), 6.73 (d,1H), 6.16 (d, 1H), 5.70 (t, 1H), 5.11 (s, 2H), 4.16 (q, 2H), 3.05 (dt,2H), 2.34 (s, 3H), 1.21 (t, 3H), 1.02 (t, 3H).

b) 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-aceticacid, ethyl ester

To a solution of the product from part (a) (0.5 g) in dichloromethane(10 ml) was added triethylamine (0.18 ml) and acetyl chloride (0.1 ml),the reaction was stirred at room temperature for 30 minutes. The mixturewas then adsorbed onto silica gel and purified by flash columnchromatography (33% EtOAc/hexane as eluent) to give the subtitlecompound (0.52 g).

¹H NMR (DMSO) δ 9.51 (s, 1H), 7.46 (d, 1H), 7.34-7.27 (m, 3H), 7.11 (t,1H), 6.97 (d, 2H), 5.24 (s, 2H), 4.18 (q, 2H), 2.39 (s, 3H), 1.86 (s,3H), 1.21 (t, 3H).

c)4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The subtitle compound was prepared by the method of example 20 part (c)using the product from part (b). Used without further characterisationin part (d).

d)4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the product from part (c). Product was purified using reversephase preparative HPLC (eluent MeCN/NH₃(aq)).

¹H NMR (DMSO) δ 10.34 (1H, s), 8.01 (1H, d), 7.77 (2H, dt), 7.67 (2H,m), 7.29 (1H, d), 7.19 (1H, t), 4.82 (2H, s), 2.66 (3H, s), 2.06 (3H,s).

APCI− (M−H) 419

EXAMPLE 223-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

a) 4-amino-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, ethyl ester

A suspension of the product from example 20 part (c) (1 g) in glacialacetic acid (50 ml) was stirred in the presence of 5% Pt/C (0.5 g) under3 bar pressure of H₂ for 24 hours. The catalyst was removed byfiltration and the filtrates concentrated in vacuo. Purification byflash column chromatography (20% EtOAc/hexane as eluent) gave thesubtitle compound (0.45 g).

¹H NMR (DMSO) δ 7.89 (2H, dt), 7.66 (2H, dt), 6.96 (1H, t), 6.72 (1H,d), 6.45 (1H, d), 5.96 (2H, s), 5.13 (2H, s), 4.14 (2H, q), 2.63 (3H,s), 1.18 (3H, t)

3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid, ethyl ester was isolated as a by product from the reaction.

¹H NMR (DMSO) δ 7.83 (2H, dd), 7.67 (2H, dt), 7.06 (1H, t), 6.78 (1H,d), 6.72 (1H, t), 6.31 (1H, d), 5.16 (2H, s), 4.15 (2H, q), 3.12 (2H,dt), 2.65 (3H, s), 1.28-1.16 (6H, m)

b)3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

To a solution of the product from part (a) (0.2 g) in acetonitrile (10ml) was added triethylamine (72 ul) and methane sulfonylchloride (41ul), the reaction was heated to reflux overnight. The mixture was thenadsorbed onto silica gel and purified by flash column chromatography(33% EtOAc/hexane as eluent) to give the subtitle compound (0.18 g)

¹H NMR (DMSO) δ 9.83 (1H, s), 7.84 (2H, d), 7.71 (2H, d), 7.40 (1H, d),7.33-7.27 (2H, m), 5.31 (2H, s), 4.17 (2H, q), 2.99 (3H, s), 2.68 (3H,s), 1.20 (3H, t)

c)3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the product of part (b). The product was recystallised fromboiling aqueous ethanol.

¹H NMR (DMSO) δ 9.84 (1H, s), 7.84 (2H, dt), 7.71 (2H, dt), 7.40 (1H,dd), 7.33-7.27 (2H, m), 5.15 (2H, s), 2.98 (3H, s), 2.68 (3H, s)

MS: APCI− [M−H] 455

m.p. dec>237° C.

EXAMPLE 233-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid

a)3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d)using the by product from example 22 part (a). Product was purifiedusing reverse phase preparative HPLC.

NMR (DMSO) δ 7.83 (2H, dt), 7.65 (2H, dt), 7.02 (1H, t), 6.73-6.69 (2H,m), 6.27 (1H, d), 4.68 (2H, s), 3.12 (2H, dt), 2.62 (3H, s), 1.25 (3H,t)

MS: APCI− [M−H] 405

EXAMPLE 243-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid

a) 3-[(2,6-Dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 2,6-dichlorobenzenethiol(0.36 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml).After 1 h the solution was purified by reverse phase HPLC. The solventwas evaporated in vacuo and the oily residue treated with ether to givea solid. Filtered off and dried to yield the title compound as a whitesolid (0.22 g).

MS: APCI− [M−H]⁻ 378

¹H NMR δ_((DMSO)) 7.49 (2H, d), 7.29 (1H, m), 7.24 (1H, d), 7.13 (1H,s), 6.88 (1H, d), 4.81 (2H, s), 2.44 (3H, s), 2.29 (3H, s)

b) 3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid

3-Chlorobenzenecarboperoxoic acid (0.34 g) was added to a solution ofthe product from example 24 step a) (0.18 g) in acetonitrile (5 ml) andwater (0.5 ml). The reaction was stirred for 1 h, 1M aqueous sodiumthiosulphate (2 ml) added and stirred for a further 15 min. The mixturewas filtered, purified by reverse phase HPLC and evaporated in vacuo toyield the title compound as a white solid (40 mg).

MS: APCI− 410 [M−H]⁻

¹H NMR δ_((DMSO)) 7.64-7.60 (2H, m), 7.57-7.51 (1H, m), 7.45 (1H, s),7.42 (1H, d), 7.03 (1H, d), 5.01 (2H, s), 2.60 (3H, s), 2.33 (3H, s)

EXAMPLE 253-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic acid

a) 4-bromo-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole

The subtitle compound was prepared by the method of example 2 part (a)using (3-bromophenyl)-hydrazine hydrochloride. Product purified usingFlash column chromatography (10% EtOAc/hexane as eluent).

¹H NMR (CDCl₃) δ 7.31 (1H, s), 7.30 (2H, d), 7.13 (2H, dt), 7.02 (1H,t), 6.94 (2H, dt), 2.52 (3H, s).

b) 4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,1,1-dimethylethyl ester

The subtitle compound was prepared by the method of example 20 part (b)using the product of part (a) and t-butylbromoacetate. Product waspurified using Flash column chromatography (10% EtOAc/hexane as eluent).

¹H NMR (CDCl₃) d 7.31 (1H, dd), 7.21 (1H, dd), 7.14-7.10 (2H, m), 7.05(1H, t), 6.94-6.91 (2H, m), 4.77 (2H, s), 2.49 (3H, s), 1.43 (9H, s).

c) 3-[(4-chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic acid,1,1-dimethylethyl ester

To a solution of the product of part (b) (0.5 g) in ethanol (0.8 ml) andtoluene (3 ml) was added 2 M sodium carbonate solution in water (1.4ml), phenylboronic acid (0.131 g) andtetrakis(triphenylphosphine)palladium(0) (1.2 g). The reaction washeated to reflux for 2 hours, cooled and concentrated in vacuo. Theresidue was purified by flash column chromatography to give the subtitlecompound (0.4 g).

¹H NMR (DMSO) d 7.53 (1H, d), 7.25-7.18 (2H, m), 7.15-7.09 (6H, m), 6.87(1H, d), 6.54 (2H, m), 5.17 (2H, s), 2.39 (3H, s), 1.43 (9H, s).

d) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-aceticacid, 1,1-dimethylethyl ester

The subtitle compound was prepared by the method for example 20 part (c)using the product from part (c). The product was used without furthercharacterisation in part (e).

e) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-aceticacid

The title compound was prepared by the method of example 2 part (d) withthe addition that the reaction mixture was heated to reflux for 20minutes. Product was purified using reverse phase preparative HPLC(eluent MeCN/NH₃(aq)).

¹H NMR (DMSO) δ 7.51-7.41 (3H, m), 7.24-7.12 (4H, m), 7.06 (2H, t), 6.82(2H, d,), 6.75 (1H, d), 4.68 (2H, s), 2.73 (3H, s)

MS: APCI− [M−H] 438

EXAMPLE 263-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-4H-indole-1-acetic acid,ammonium salt

a) 5-fluoro-2-methyl-1H-indole-1-acetic acid methyl ester

A mixture of 5-fluoro-2-methylindole (2.4 g), cesium carbonate (16.6 g)and methyl bromoacetate (5.4 ml) in acetone 240 ml was stirred andheated under reflux for 16 h. The solvent was removed, water and ethylacetate were added and the organic phase separated.

The aqueous phase was re-extraced with ethyl acetate and the combinedorganic solution dried and concentrated to a solid. Purification byflash chromaography using dichloromethane:ethylacetate gave the subtitlecompound as a solid (2.9 g)

MS: APCI+ [M+H] 222

b) 5-fluoro-2-methyl-1H-indole-1-acetic acid

The product from step a) was dissolved in THF (30 ml) and a solution ofLiOH.H20 (0.91 g) in H₂O (10 ml) was added. After 24 h the solvent wasremoved, 10% (aq) HCl and ethyl acetate were added and the organic phaseseparated. The aqueous phase was re-extraced with ethyl acetate and thecombined organic solution washed with brine, dried and concentrated toan oil. Purification by flash chromaography usingdichloromethane:ethylacetate gave the subtitle compound as a yellowpowder (1.2 g).

MS: APCI [M−H]⁻ 206

c) 3-[(4-chlorophenyl)thio]-5-fluoro-2-methyl-1H-indole-1-acetic acid

Iodine (0.98 g) was added to a solution of 4-chlorolbenzenethiol (0.55g) and the product from step b) (0.4 g) in NMP (5 ml). The solution wasstirred for 24 h and the crude product purified by reverse phasechromatography to give the subtitle compound as a solid (0.29 g)

MS: APCI [M−H]⁻ 348/50

¹H NMR (DMSO) δ 7.4 (1H, m), 7.25 (2H, d), 7.0-6.9 (4H, m), 4.59 (2H,s), 2.37 (3H, s).

d) 3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-aceticacid, ammonium salt

3-Chlorobenzenecarboperoxoic acid (0.4 g) was added to a solution of theproduct from step c) (0.19 g) in acetonitrile (4 ml). The reaction wasstirred for 3 h, 1M aqueous sodium thiosulphate (5 ml) was added andstirred for a further 15 min, 10% aqu HCl and ethyl acetate were addedand the organic phase separated. The aqueous phase was re-extracted withethyl acetate and the combined organic solution washed with brine, driedand concentrated to a solid which was purified by reverse phasechromatography to give the title compound as a solid (0.12 g)

MS: APCI [M−H]⁻ 380/82

¹H NMR (DMSO) δ 7.94 (2H, m), 7.62 (2H, m), 7.6-7.55 (2H, m), 7.4-6.8(1H bs), 7.05 (1H, dt), 4.8 (2H, s), 2.61 (3H, s).

EXAMPLE 273-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic acid,ammonium salt

a) 3-[(3-chlorophenyl)thio]-5-fluoro-2-methyl-1H-indole-1-acetic acid

Prepared by the method of example 26 step c) using the product ofexample 26 step b) (0.55 g), iodine (0.98 g) and 3-chlorolbenzenethiolto give the subtitle compound as a solid (0.25 g)

MS: APCI [M−H]⁻ 348/50 ¹H NMR (DMSO) δ 7.4 (1H, m), 7.2 (1H, m), 7.16(1H, m), 7.0-6.95 (4H, m), 4.57 (2H, s), 2.28 (3H, s)

b) 3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-aceticacid, ammonium salt

Prepared by the of example 26 step d) using the product of example 27step a) (0.15 g) and 3-chlorobenzenecarboperoxoic acid (0.32 g) to givethe title compound as a solid (0.09 g).

MS: APCI [M−H]⁻ 380/82

¹H NMR (DMSO) δ 7.94 (2H, m), 7.7 (1H, m), 7.6 (2H, m), 7.55 (1H, m),7.2-7.0 (1H bs), 7.05 (1H, dt), 4.79 (2H, s), 2.63 (3H, s).

EXAMPLE 285-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-aceticacid, ammonium salt

a)5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]thio]-1H-indole-1-aceticacid

Prepared by the method of example 26 step c) using the product ofexample 26 step b) (0.55 g), iodine (0.98 g) and4-trifluoromethylbenzenethiol (0.67 g) to give the subtitle compound asa solid (0.25 g).

MS: APCI [M−H]^(− N)382

¹H NMR (DMSO) δ 7.57 (3H, m), 7.05 (2H, m), 7.02 (2H, m), 5.0 (2H, s),2.4 (3H, s)

b)5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-aceticacid, ammonium salt

Prepared by the method of example 26 step d) using the product ofexample 28 step a) (0.17 g) and 3-chlorobenzenecarboperoxoic acid (0.33g) to give the title compound as a solid (0.11 g).

MS: APCI [M−H]⁻ 414

¹H NMR (DMSO) δ 8.18 (2H, d), 7.95 (2H, d), 7.65-58 (2H, m), 7.2-6.9(1H, bs), 7.14-7.09 (1H, m), 5.02 (2H, s), 2.67 (3H, s).

Pharmacological Data Ligand Binding Assay

[³H]PGD₂ was purchased from Perkin Elmer Life Sciences with a specificactivity of 100-210 Ci/mmol. All other chemicals were of analyticalgrade.

HEK cells expressing rhCRTh2/Gα16 were routinely maintained in DMEMcontaining 10% Foetal Bovine Serum (HyClone), 1 mg/ml geneticin, 2 mML-glutamine and 1% non-essential amino acids. For the preparation ofmembranes, the adherent transfected HEKcells were grown to confluence intwo layer tissue culture factories (Fisher, catalogue numberTKT-170-070E). Maximal levels of receptor expression were induced byaddition of 500 mM sodium butyrate for the last 18 hours of culture. Theadherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell factory) and detached by the addition of 50 ml per cellfactory of ice-cold membrane homogenisation buffer [20 mM HEPES (pH7.4), 0.1 mM dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonylfluoride and 100 μg/mlbacitracin]. Cells were pelleted by centrifugationat 220×g for 10 minutes at 4° C., re-suspended in half the originalvolume of fresh membrane homogenisation buffer and disrupted using aPolytron homogeniser for 2×20 second bursts keeping the tube in ice atall times. Unbroken cells were removed by centrifugation at 220×g for 10minutes at 4° C. and the membrane fraction pelleted by centrifugation at90000×g for 30 minutes at 4° C. The final pellet was re-suspended in 4ml of membrane homogenisation buffer per cell factory used and theprotein content determined. Membranes were stored at −80° C. in suitablealiquots.

All assays were performed in Corning clear bottomed, white 96-well NBSplates (Fisher). Prior to assay, the HEK cells membranes containingCRTh2 were coated onto SPA PVT WGA beads (Amersham). For coatingmembranes were incubated with beads at typically 25 μg membrane proteinper mg beads at 4° C. with constant agitation overnight. (The optimumcoating concentrations were determined for each batch of membranes) Thebeads were pelleted by centrifugation (800×g for 7 minutes at 4° C.),washed once with assay buffer (50 mM HEPES pH 7.4 containing 5 mMmagnesium chloride) and finally re-suspended in assay buffer at a beadconcentration of 10 mg/ml.

Each assay contained 20 μl of 6.25 nM [³H]PGD₂, 20 μl membrane saturatedSPA beads both in assay buffer and 10 μl of compound solution or13,14-dihydro-15-keto prostaglandin D₂ (DK-PGD₂, for determination ofnon-specific binding, Cayman chemical company). Compounds and DK-PGD₂were dissolved in DMSO and diluted in the same solvent to 100× therequired final concentration. Assay buffer was added to give a finalconcentration of 10% DMSO (compounds were now at 10× the required finalto concentration) and this was the solution added to the assay plate.The assay plate was incubated at room temperature for 2 hours andcounted on a Wallac Microbeta liquid scintillation counter (1 minute perwell).

Compounds of formula (I) have an IC₅₀ value of less than (<) 10 μM.Specifically example 2 has a pIC₅₀=8.1 example 6 has a pIC₅₀=7 andexample 7 has a pIC₅₀=6.6

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

in which: n represents 1 or 2; R¹ is one or more substituentsindependently selected from halogen, CN, nitro, SO₂R⁴, OR⁴, SR⁴, SOR⁴,SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, aryl, heteroaryl,C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁₋₆alkyl, the latter five groups beingoptionally substituted by one or more substituents independentlyselected from halogen, OR⁷ and NR⁸R⁹, NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1or 2; R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, COR⁴ or C₁₋₇alkyl,the latter group being optionally substituted by one or moresubstituents independently selected from halogen atoms, OR⁸ and NR⁵R⁶,S(O)_(x)R⁷ where x is 0, 1 or 2; R³ is aryl or a 5-7 membered aromaticring containing one or more heteroatoms selected from N, S and O, eachof which is optionally substituted by one or more substituentsindependently selected from halogen, CN, nitro, SO₂R⁴, OH, OR⁴, SR⁴,SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl, the latter three groups beingoptionally substituted by one or more substituents independentlyselected from halogen atoms, OR' and NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1or 2; R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl, all of which maybe optionally substituted by one or more substituents independentlyselected from halogen atoms, aryl, heteroaryl, OR¹⁰ andNR¹¹R¹²S(O)_(x)R¹³ (where x=0, 1 or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵,SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro; R⁵ and R⁶ independently represent ahydrogen atom, a C₁-C₆ alkyl group, an aryl, or a heteroaryl, the latterthree of which may be optionally substituted by one or more substituentsindependently selected from halogen atoms, aryl, OR¹³ and NR¹⁴R¹⁵,CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro; or R⁵ and R⁶together with the nitrogen atom to which they are attached can form a3-8 membered saturated heterocylic ring optionally containing one ormore atoms selected from O, S(O)_(x) where x is 0, 1 or 2, NR¹⁶, and thering itself optionally substituted by C₁-C₃ alkyl; R⁷ and R¹³independently represent a C₁-C₆ alkyl group, an aryl or heteroaryl groupall of which may be optionally substituted by halogen atoms; R⁸represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionally substitutedby halogen atoms, aryl or heteraryl groups, both of which may also beoptionally substituted by one or more fluorine atoms); an aryl or aheteroaryl group, which may be optionally substituted by one or morehalogen atoms; each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independentlyrepresents a hydrogen atom, C₁-C₆ alkyl, an aryl or a heteroaryl group(all of which may be optionally substituted by one or more halogenatoms); and R¹⁶ is hydrogen, C₁₋₄ alkyl, —C(O)C₁-C₄ alkyl,C(O)YC₁-C₄alkyl, Y is O or NR⁷. or a pharmaceutically acceptable salt orsolvate thereof.
 2. A compound according to claim 1 in which n is
 2. 3.A compound according to claim 1 in which R¹ is halogen, nitrile,C₁₋₆alkyl or SO₂R⁴, NO₂, NR⁹COR⁴, NR⁹SO₂R⁴, aryl, NR⁵R⁶.
 4. A compoundaccording to claim 1 in which the substituent(s) is/are in the 4- and/or5-position.
 5. A compound according to claim 1 in which R² is C₁₋₆alkyl.6. A compound according to claim 4 in which R³ is phenyl substituted byhalogen.
 7. A compound according to claim 1 selected from:3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-aceticacid;5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-aceticacid; 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-aceticacid; 3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-aceticacid; 3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-aceticacid; 5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid, 4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid; 3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic acid;3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic acid;4-(Acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceticacid;3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid; 3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-aceticacid; 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-aceticacid 3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-aceticacid, 3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-aceticacid,5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-aceticacid, and pharmaceutically acceptable salts thereof.
 8. (canceled)
 9. Amethod of treating a disease mediated by prostaglandin D2, whichcomprises administering to a patient a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable salt asdefined in claim
 1. 10. A method according to claim 9 where the diseaseis asthma or rhinitis.
 11. Use of a compound of a compound of formula(I), or a pharmaceutically acceptable salt as defined in claim 1, in themanufacture of a medicament for treating a disease mediated byprostaglandin D2. 12-13. (canceled)
 14. A process for the preparation ofa compound of formula (I) of claim 1 which comprises reaction of acompound of formula (II): (a) oxidation of a compound of formula (II):

in which R¹⁷ is hydrogen or alkyl and R¹, R² and R³ are as defined inclaim 1 or are protected derivatives thereof, or (b) reaction of acompound of formula (III):

in which R¹, R² and R³ are as defined in claim 1 or are protectedderivatives thereof, with a compound of formula (IV):R¹⁸—O(CO)CH₂-L  (IV) where R¹⁸ is an alkyl group and L is a leavinggroup in the presence of a base, and optionally thereafter (a) or (b) inany order: hydrolysing the ester group R¹⁷ or R¹⁸ to the correspondingacid removing any protecting group forming a pharmaceutically acceptablesalt.